Circumventing cellular immunity by miR142-mediated regulation sufficiently supports rAAV-delivered OVA expression without activating humoral immunity

UMMS Affiliation

Horae Gene Therapy Center; Department of Microbiology and Physiological Systems; Li Weibo Institute for Rare Diseases Research; Department of Pediatrics

Publication Date


Document Type



Genetic Phenomena | Genetics and Genomics | Hemic and Immune Systems | Immunoprophylaxis and Therapy | Nucleic Acids, Nucleotides, and Nucleosides | Therapeutics


Recombinant adeno-associated virus (rAAV)-mediated gene delivery can efficiently target muscle tissues to serve as "biofactories" for secreted proteins in prophylactic and therapeutic scenarios. Nevertheless, efficient rAAV-mediated gene delivery is often limited by host immune responses against the transgene product. The development of strategies to prevent anti-transgene immunity is therefore crucial. The employment of endogenous microRNA (miRNA)-mediated regulation to detarget transgene expression from antigen presenting cells (APCs) has shown promise for reducing immunogenicity. However, the mechanisms underlying miRNA-mediated modulation of anti-transgene immunity by APC detargeting are not fully understood. Using the highly immunogenic ovalbumin (OVA) protein as a proxy for foreign antigens, we show that rAAV vectors containing miR142 binding sites efficiently repress co-stimulatory signals in dendritic cells, significantly blunt the cytotoxic T cell response, allow for sustained transgene expression in skeletal myoblasts, and attenuate clearance of transduced muscle cells in mice. Furthermore, the blunting of humoral immunity against circulating OVA correlates with detargeting of OVA expression from APCs. This demonstrates that incorporating APC-specific miRNA binding sites into rAAV vectors provides an effective strategy for reducing transgene-specific immune response. This approach holds promise for clinical applications where the safe and efficient delivery of a prophylactic or therapeutic protein is desired.


Antigen presenting cells, Gene therapy, Immunology, Muscle, Therapeutics

DOI of Published Version



JCI Insight. 2019 May 21;5. pii: 99052. doi: 10.1172/jci.insight.99052. Link to article on publisher's site

Journal/Book/Conference Title

JCI insight


Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID